Time-restricted feeding reverses kidney fibrosis through reducing CD8+ T cell infiltration in obese mice

Obesity is a major risk factor for chronic kidney disease. Time-restricted feeding (TRF) shows promise to reduce kidney inflammation in chronic kidney disease. We hypothesized that TRF blunts kidney fibrosis in obese mice by mitigating T cell inflammation. We used a diet-induced obese mouse model fed a high-fat diet (DIO; 45% fat) ad libitum for 18 weeks followed by 2 weeks of TRF or ad libitum high-fat feeding. We found that TRF reversed kidney fibrosis as well as reduced kidney CD8+ T cells in DIO mice. Our study also reveals that DIO mice had increased kidney CD8+ T cell infiltration from the small intestine that was blunted with TRF. Furthermore, anti-CD8 intervention in DIO showed reduced kidney fibrosis and damage compared with anti-IgG-treated DIO mice. Single-cell RNA-seq data reveal that DIO increased, while TRF reduced, the frequency of a specific cluster of CD8+ T cells that featured high expression of exhaustion/activation genes. Spatial analyses showed DIO mice had significant infiltration of PD-1+CD8+ T cells near CD31+ endothelial cells that was diminished by TRF. In conclusion, this study shows that TRF reversed kidney fibrosis through reducing CD8+ T cell infiltration in obese mice.